The general aim of this project is to elucidate the mechanism of action of cardiac glycosides at the cellular and the molecular levels. Since there is increasing evidence that the Na ion, K ion-ATPase complex of the cell membrane is the receptor for the toxic and the therapeutic effects of cardiac glycosides, our attention is focussed on the interactions of these drugs with this enzyme complex. The three specific research projects are as follows: (1) We are attempting to determine the mechanism and the site of action of these drugs within the partially purified enzyme complex through the study of the kinetic of drug effects on several partial reactions of the ATPase. (2) We are determining the organization of the components of this complex within the intact membrane; and the manner by which each component is involved in active translocation of Na ion and K ion across the plasma membrane. (3) We are trying to find the precise mechanism by which the interaction of cardiac glycosides with the Na ion, K ion-ATPase leads to the partial inhibition of glycolysis in the red cells and the cardiac muscle.